Ushaku Lee

Kanagawa Dental University, Йокосука, Kanagawa, Japan

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Publications (15)33.05 Total impact

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    ABSTRACT: NK4 inhibits vascularisation in tumour tissues, thereby arresting tumour growth. However, the antitumour efficacy of individual antiangiogenic molecules expressed in vivo is not sufficiently potent to induce regression in animal models. One of the strategies to overcome this disadvantage is to use chemotherapy. This study evaluated the efficacy of combining NK4 gene therapy with cisplatin to treat experimental squamous cell carcinomas. For gene therapy, biodegradable cationised gelatin microspheres were used for the controlled release of NK4 plasmid DNA. A combined regimen of antiangiogenic gene therapy and low-dose cisplatin led to a marked decrease in tumour volume and vascularity, and caused increased apoptosis compared to NK4 gene therapy alone. Moreover, combination treatment of NK4 gene therapy and low-dose cisplatin dramatically inhibited the formation of lung metastases. NK4 gene therapy combined with low-dose cisplatin may be an effective regimen for treating oral squamous cell carcinoma.
    No preview · Article · Jan 2011 · Anticancer research
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    ABSTRACT: Cancer cells metastasize by entering the lymphatic system. Regional lymph-node dissemination is the first detectable step in the metastasis of oral squamous cell carcinoma (SCC) and is highly correlated to the prognosis of the disease. Cold shock domain protein A (CSDA) is a DNA-binding protein that represses angiogenesis and lymphangiogenesis by directly binding to hypoxia response element (HRE) and serum response element (SRE). In our study we used the cell line NR-S1M, a mouse SCC model with a high rate of lymph-node metastasis. Into these cells we transfected the expression-plasmid coding for full-length mouse CSDA. Of importance, we showed that overexpression of CSDA significantly inhibits the production of VEGF-A and VEGF-C in NR-S1M cells. The overexpression of CSDA in NR-S1M cells inhibited tumor growth, inhibited regional lymph-node metastasis, and reduced the density of blood vessels and lymphatic vessels in the primary tumors in vivo. Our results support the hypothesis that VEGF-A and VEGF-C are crucial regulators of angiogenesis and lymphangiogenesis in NR-S1M cells. Therefore, they are promising targets for CSDA overexpression gene therapy to inhibit tumor growth and lymph-node metastasis in SCC.
    No preview · Article · Oct 2010 · Clinical and Experimental Metastasis
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    ABSTRACT: Inverted ductal papilloma (IDP) is a type of ductal papilloma arising in ducts of minor salivary glands. Very few cases, and no cases in Japan, have been reported. Reported herein is a case of IDP with a review of the literature. The patient was a 49-year-old man presenting with a lump in the right buccal mucosa of the premolar area of the mandible. The tumor was excised en bloc after a biopsy diagnosis of IDP. On the surface of the covering epithelium, an opening was seen to be filled with mucinous material. On cut surface the opening led to the tumor cavity. The major portion of the tumor parenchyma was made up of papillary proliferation of basaloid squamous cells. Some crypts, microcysts, and mucous cells were seen. There were no findings suggestive of a malignant tumor. The patient's postoperative course was uneventful and there has been no recurrence after 1 year's follow up. Immunohistochemical analysis of the present case supports the hypothesis that IDP originates from squamous metaplasia and proliferation of minor salivary gland duct cells.
    No preview · Article · Sep 2006 · Pathology International
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    ABSTRACT: Double-stranded RNA (dsRNA) plays a major role in RNA interference (RNAi), a process in which segments of dsRNA are initially cleaved by the Dicer into shorter segments (21-23 nt) called small interfering RNA (siRNA). These siRNA then specifically target homologous mRNA molecules causing them to be degraded by cellular ribonucleases. RNAi down regulates endogenous gene expression in mammalian cells. Vascular endothelial growth factor (VEGF) is a key molecule in vasculogenesis as well as in angiogenesis. Tumor growth is an angiogenesis-dependent process, and therapeutic strategies aimed at inhibiting angiogenesis are theoretically attractive. To investigate the feasibility of using siRNA for VEGF in the specific knockdown of VEGF mRNA, thereby inhibiting angiogenesis, we have performed experiments with a DNA vector based on a siRNA system that targets VEGF (siVEGF). It almost completely inhibited the expression of three different isoforms (VEGF120, VEGF164 and VEGF188) of VEGF mRNA and the secretion of VEGF protein in mouse squamous cell carcinoma NRS-1 cells. The siVEGF released from cationized gelatin microspheres suppressed tumor growth in vivo. A marked reduction in vascularity accompanied the inhibition of a siVEGF-transfected tumor. Fluorescent microscopic study showed that the complex of siVEGF with cationized gelatin microspheres was still present around the tumor 10 days after injection, while free siVEGF had vanished by that time. siVEGF gene therapy increased the fraction of vessels covered by pericytes and induced expression of angiopoietin-1 by pericytes. These data suggest that cationized-gelatin microspheres containing siVEGF can be used to normalize tumor vasculature and inhibit tumor growth in a NRS-1 squamous cell carcinoma xenograft model.
    Preview · Article · May 2006 · Cancer Science
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    ABSTRACT: A 38-year-old man with severely limited mouth opening caused by unilateral coronoid process enlargement due to osteochondroma is reported.
    No preview · Article · Jun 2005 · Asian Journal of Oral and Maxillofacial Surgery
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    ABSTRACT: NKT cells produce large amounts of cytokines associated with both the Th1 (IFN-gamma) and Th2 (IL-4) responses following stimulation of their invariant Valpha14 Ag receptor. The role of adhesion molecules in the activation of NKT cells by the Valpha14 ligand alpha-galactosylceramide (alpha-GalCer) remains unclear. To address this issue, LFA-1-/- (CD11a-/-) mice were used to investigate IL-4 and IFN-gamma production by NKT cells following alpha-GalCer stimulation. Intriguingly, LFA-1-/- mice showed increased IL-4, IL-5, and IL-13 production and polarized Th2-type responses in response to alpha-GalCer in vitro and in vivo. Furthermore, the Th2-specific transcription factor GATA-3 was up-regulated in alpha-GalCer-activated NKT cells from LFA-1-/- mice. These results provide the first genetic evidence that the adhesion receptor LFA-1 has a crucial role in Th2-polarizing functions of NKT cells.
    Preview · Article · Nov 2004 · The Journal of Immunology
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    ABSTRACT: The possibility of inhibiting tumor growth by blocking the formation of new tumor vessels has recently received attention. Antiangiogenic tumor therapies have recently attracted intense interest because of their direct endothelial targeting and the absence of drug resistance. Local antiangiogenic gene therapy for cancer offers a potential way to achieve sustained therapeutic release of antiangiogenic substances. As a step toward this goal, we used liposomes complexed to angiostatin cDNA and targeted to human squamous cell carcinoma cell lines in vivo. Tumor cells expressing angiostatin after local gene transfer showed markedly reduced vascularity and contained many apoptotic tumor cells. These results demonstrate the potential utility of liposome-derived angiostatin for adjuvant therapy of oral cancer in humans.
    No preview · Article · Oct 2002 · Oral Oncology
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    ABSTRACT: Interleukin 12 (IL-12)-activated NK1.1+TCRα β+ (NKT2) and NK1.1+TCRα β– (NK) cells exhibit cytotoxic activity against a wide variety of tumor cells in the absence of prior sensitization. Here we demonstrate that the integrin adhesion receptor LFA-1 (CD11a / CD18) regulates the cytotoxic activity of IL-12-activated NKT and NK cells against YAC-1 and EL-4 tumor cells. Differentiation in vivo and the expression of the cytolytic effector molecules perforin and Fas-L were comparable in both IL-12-activated NKT and NK cells from LFA-1– / – and LFA-1+ / + mice. However, LFA-1– / – IL-12-activated NKT and NK cells showed impaired conjugate formation with target cells. These results provide the first genetic evidence for a role for an adhesion receptor in killing by IL-12-activated NK cells.
    No preview · Article · Nov 2000 · European Journal of Immunology

  • No preview · Article · Jan 2000
  • U Lee · K Santa · S Habu · T Nishimura
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    ABSTRACT: Freshly isolated CD8+ T cells, but not CD4+ T cells, contained 20-30% of asialo GM1+ (ASGM1+) T cells which were distinct from ASGM1+NK1.1+ natural killer cells. This novel ASGM1+CD8+ T cell subpopulation showed a strong proliferative response to interleukin-12 (IL-12) in the presence of IL-2. Culture of ASGM1+CD8+ T cells with IL-12 plus IL-2 allowed the generation of anomalous killer T cells concomitantly with the accumulation of cytolytic molecules. Moreover, ASGM1+CD8+ T cells produced high levels of interferon-gamma (IFN-gamma), but not IL-4, upon stimulation with IL-12 plus IL-2. Such immune responses were not observed in ASGM1-CD8+ T cell subpopulations constituting the majority of CD8+ T cells. These results demonstrated that ASGM1+CD8+ T cells are a novel subpopulation of IL-12-responsive and IFN-gamma-producing killer T cell precursors.
    No preview · Article · Jun 1996 · Japanese journal of cancer research: Gann
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    ABSTRACT: Freshly isolated CD8+ T cells, but not CD4+ T cells, contained 20–30% of asialo GM1+ (ASGM1+) T cells which were distinct from ASGM1+NK1.1+ natural killer cells. This novel ASGM1+CD8+ T cell subpopulation showed a strong proliferative response to interlenkin-12 (IL-12) in the presence of IL-2. Culture of ASGM1+CD8+ T cells with IL-12 plus IL-2 allowed the generation of anomalous killer T cells concomitantly with the accumulation of cytolytic molecules. Moreover, ASGM1+CD8+ T cells produced high levels of interferon-γ (IFN-γ), but not IL-4, upon stimulation with IL-12 plus IL-2. Such immune responses were not observed in ASGM1− CD8+ T cell snbpopulations constituting the majority of CD8+ T cells. These results demonstrated that ASGM1+CD8+ T cells are a novel subpopulation of IL-12-responsive and IFN-γ-producing killer T cell precursors.
    Full-text · Article · May 1996 · Cancer Science
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    ABSTRACT: この報告はlimphokine activated killer (LAK) 細胞を使った免疫療法と放射線療法の組み合わせにより治療した口腔癌の4症例について述べている。この研究では, われわれは誘導されたLAK細胞の表面フェノタイプと細胞障害活性を分析し, 末梢血リンパ球 (以下PBL) もまた口腔癌患者に対してLAK細胞投与前後で分析された。さらに, われわれは免疫組織化学的手法で抗腫瘍効果のあった部位の変化を観察した。PBLは口腟癌患者より得, 17~24日間の培養でrIL-2 (塩野義製薬, 700JRU) と抗CD3 moAb (25ng/ml) でLAK細胞を誘導した。患者の腫瘍領域動脈への投与は2回の培養で得られたLAK細胞を8回に分け, それぞれの投与の間隔は2~3日で6.2~17×109LAK細胞がそれぞれの患者に投与された。細胞障害活性は4時間の51Cr遊離試験法を行い, K-562細胞 (E/T=5/1) で測定された。フェノタイプの性格付けは2色の種々のモノクローナル抗体を用いてフローサイトメトリーにより測定された。この時測定された細胞はLAK細胞と口腔癌患者へのLAK細胞投与前後のPBLであった。結果は, 細胞障害活性はLAK細胞の平均で74.6%であった。LAK細胞の投与前後のPBLの細胞障害活性はin vitroの測定で低下傾向を示した。フェノタイプの性格付けでは, LAK細胞の平均でCD8+/CD11-細胞とCD3+/HLA-DR+細胞が増加した。LAK細胞投与前後でPBLの平均ではCD4+細胞が増加しCD8+/CD11-細胞, CD3+/HLA-DR+細胞そしてCD8+/CD11+細胞が減少していた。LAK細胞投与後では, 症例1においてUCHL-1+細胞とHLA-DR+細胞が腫瘍周囲に著明に増加した。
    No preview · Article · Jan 1996

  • No preview · Article · Jan 1996 · Immunology Letters
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    ABSTRACT: A single i.p. administration of IL-12 (2000 U/mouse) into the mice caused the elevation of serum IFN-gamma activity and the generation of killer cells which can lyse various kinds of tumor cells including both NK-sensitive and -resistant tumor cells. Such in vivo induced killer cells were not detected in the mice treated with the same dose of IL-2. The generation of IL-12-activated killer cells (IL-12AK) peaked at day 1 and sustained their cytotoxicity until day 3 after IL-12 administration. The generation of IL-12AK was inhibited by in vivo administration of anti-asialo GM1 (ASGM1) Ab but not anti-CD4 or anti-CD8 mAbs, suggesting that the precursor cells for IL-12AK were ASGM1+CD4-CD8- NK cells. The phenotypic characterization of in vivo induced effector cells with IL-12AK activity was carried out by separating the cells with FACStar. The IL-12AK activity was highly enriched in ASGM1+CD4-8- or NK1.1+CD4-8- NK cells, but not in CD8+ T cells and CD4+ T cells. The IL-12AK cells were also generated in tumor-inoculated mice. In parallel with the in vivo generation of IL-12AK generation, the growth of i.p. inoculated MBL-2 lymphoma cells was markedly inhibited by the administration with IL-12. The in vivo antitumor activity of IL-12 was blocked by the administration of anti-ASGM1 but not anti-CD4 or anti-CD8 mAbs in concomitant with the decrease of IL-12AK generation. From these results, it was indicated that ASGM1+NK1.1+CD4-8- NK type IL-12AK cells might play an important role in IL-12-induced local therapy of tumor in vivo.
    No preview · Article · Jan 1996 · Immunology Letters
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    ABSTRACT: It is an important issues to investigate an efficient methods to induce antitumor effector T cells from peripheral blood lymphocytes of tumor patients for the development of a novel tumor immunotherapy. We established a large scale culture system of human CD4+ helper/killer T cells which have both helper and killer functions. Targeting of CD4+ helper/killer T cells to tumor using anti-CD3 x anti-c-erbB-2 mAb caused the lysis of tumor and triggering of IL-2 production. It was also demonstrated that culture of human CD4+ T cells with staphylococcal enterotoxin A (SEA) or IL-12 caused a selective induction of Th1 type of CD4+ helper/killer T cells. IL-12 also revealed a novel effect on CD8+CTL functions. Culture of CD8+ T cells with IL-12 resulted in the augmentation of IFN-gamma production and cytotoxicity. Moreover, culture of tumor-infiltrating lymphocytes with IL-12 caused a marked enhancement of CD8+CTL against autologous tumor cells. These findings suggest that IL-12 will become a useful cytokine for the tumor immunotherapy. In this paper, we will discuss the key role of CD4+ T cells for the induction of antitumor immunity in tumor-bearing host.
    No preview · Article · Oct 1994 · Human Cell